Thiol compounds are used in the treatment of many diseases. There are wide individual variations in the response to these agents and in the occurrence of serious drug reactions such as leukopenia. S-Methylation catalyzed by thiopurine methyltransferase (TPMT) and thiol methyltransferase (TM) is an important pathway in the metabolism of some thiol drugs. The objective of this proposal is to study the regulation of the enzymes that catalyze S-methylation in man and experimental animals and to determine whether individual variations in these activities may represent one factor in variations in response to the thiol compounds. Special emphasis will be placed on the role of inheritance in the regulation of TPMT and TMT. TPMT and TMT activities are present in the human erythrocyte (RBC), and we have developed sensitive assays for the measurement of these enzyme activities. We have also shown that human RBC TPMT activity level is inherited as an autosomal codominant trait. About 10% of the population is heterozygous for the trait and has intermediate enzyme activity and 0.3% of the population is homozygous for the trait of low activity and has undetectable RBC TPMT. It is proposed to determine whether this "pharmacogenetic" variation in human RBC TPMT reflects variation in TPMT activity in other cells and tissue and whether this genetic polymorphism might be one factor in individual variations in response to drugs such as 6-mercaptopurine. The regulation of TPMT activity in rodents will also be studied to determine the effects of inheritance, of growth and development, and of drug therapy on this enzyme activity in experimental animals. It will be determined whether inheritance may play a role in variations of human RBC membrane TMT. In addition, the regulation of TMT activity in experimental animals will be studied with special emphasis on the possible role of inheritance in this regulation. These experiments represent one step in the development of understanding of the role of variations in the activities of enzymes that catalyze S-methylation in individual differences in response to thiol medications and in the occurrence of reactions to these agents.